Sequential Infusion of Tcrαβ- and CD45RA-Depleted Haploidentical Progenitor Cells Is Safe and Allows for Rapid Immune Reconstitution in Pediatric Patients with Recurrent Hematological Malignancies

• Published in: Blood 2018-11, Vol.132 (Supplement 1), p.4574-4574
• Main Authors: Suliman, Ali Y, Li, Ying, Cullins, David, Sooter, Amanda J, Riberdy, Janice, Renee, Madden, Mamcarz, Ewelina, Qudeimat, Amr, Sharma, Akshay, Srinivasan, Ashok, Talleur, Aimee, Sunkara, Anusha, Kang, Guolian, Gottschalk, Stephen, Triplett, Brandon
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-99-110886

Background: Haploidentical hematopoietic cell transplantation (haploHCT) is an attractive option for patients, who have no suitable matched-related or -unrelated donor. While the increased alloreactivity of haploidentical grafts enhances graft-vs-leukemia effects, it also increases the risk of acute graft-vs-host disease (aGVHD). Therefore, extensive in vivo or ex vivo T-cell depletion is required to reduce the incidence of severe aGVHD. However, global T-cell depletion is associated with delayed immune recovery, serious viral infections, and relapse. To overcome this limitation, selective TCRɑß and CD45RA T-cell depletion was developed. Both aim to remove alloreactive T-cell subsets, and initial clinical experience has demonstrated the feasibility and safety of each individual approach. We reasoned that combining both approaches might further increase immune reconstitution and bolster graft-vs-leukemia effects. We therefore designed an early phase clinical study, NCT02790515, to evaluate the safety and efficacy of infusing two haploidentical allografts, one TCRɑß T-cell depleted and one CD45RA T-cell depleted, in pediatric patients with very-high risk hematological malignancies, who had recurrent disease after a previous allogeneic HCT. Methods: Patients received their second (n=16) or third (n=2) allogeneic HCT utilizing TCRαβ-depleted and CD45RA-depleted haploidentical donor progenitor cell grafts following conditioning with rabbit ATG (5mg/kg), fludarabine(150mg/m2), cyclophosphamide(60mg/kg), thiotepa(10mg/kg), and melphalan(120mg/m2) on an IRB and FDA approved single institution protocol. Tacrolimus (n=5) or sirolimus (n=13) was given for post HCT GVHD prophylaxis. At the time of HCT, 6 patients remained refractory with active disease and 9 more were in morphologic remission but had detectible minimal residual disease (MRD). Results: The conditioning regimen and progenitor cell infusions were well tolerated without dose limiting toxicities. Patients received a median T-cell dose of 11.9x106/kg (including 0.01x106 TCRαβ T cells/kg; range: 0.00-0.09) with the TCRαβ-depleted graft, and a median T-cell dose of 50.3x106/kg (including 0.00x106 CD45RA+ T-cells/kg; range: 0.00-0.02) with the CD45RA-depleted graft. All patients experienced rapid donor engraftment, with median neutrophil engraftment on Day +11 (range: 10-12). At Day +30, the median T-cell count was 91.5 TCRγδ T-cells/µl and 263 CD45RO+ (memory) T-cells/µL (range 0-2,286; Table 1). The frequenc